Abstract 3738: A Novel Protein Phosphatase in Sarcoplasmic Reticulum Calcium and Cardiac Contractile Regulation
Heart failure is one of the most significant diseases worldwide. Loss of contractility is a common feature in heart failure, although the underlying mechanisms can be diverse and complicated. Sarcoplasmic Reticulum (SR) calcium cycling defect is a major mechanism underlying contractile dysfunction. Phospholamban (PLB) mediated regulation of SERCA activity in normal and failing heart plays an important role in SR calcium cycling. We recently discovered a novel isoform of protein phosphatase 2C family which is specifically targeted on ER membrane that we named as PP2Ce and highly expressed in heart and other tissues. PP2Ce expression in neonatal myocytes selectively dephosphorylates the CaMKII dependent phospho-Thr-17 of PLB but not the PKA dependent phospho-Ser-16 of PLB. To establish the functional impact of PP2Ce activity in heart, we developed a cardiac specific PP2Ce expression transgenic mouse model (PP2Ce-Tg) and a germ-line inactivated PP2Ce mouse (PP2Ce KO). PP2Ce over-expression in PP2Ce-Tg hearts leads to significantly repressed Thr-17 phosphorylation of PLB without significant impact on the Ser-16 phosphorylation at basal condition; whereas, PP2Ce KO hearts have elevated PLB Thr-17 phosphorylation, suggesting that PP2Ce has potent and specific activity towards CaMKII dependent PLB Thr-17 site instead of PKA dependentSer-16 site of PLB in heart. PP2Ce Tg mice have significantly expedited the subsequent development of cardiac contractile dysfunction associated with higher mortality following pressure-overload by transaortic constriction (TAC); while PP2Ce KO mice delayed the development of heart failure induced by TAC compared to their corresponding control littermates. Therefore, our results suggest that PP2Ce may be a novel regulator of the PLB/SR calcium cycling regulatory machinery with a critical role in cardiac contractile regulation under physiological and pathological conditions and offer new insights to cardiac contractile regulation and failure.
This research has received full or partial funding support from the American Heart Association, National Center.